Milnacipran

• IUPAC: (±)- cis-2- (aminomethyl) - N, N -diethyl -1-phenyl cyclopropancarbamid

(1R *, 2S * ) -2 - ( aminomethyl) - N, N -diethyl -1-phenyl cyclopropancarbamid (1R, 2S)- rel -2-( aminomethyl) - N, N -diethyl -1-phenyl cyclopropancarbamid

• Latin: Milnacipranum

• C15H22N2O ( milnacipran )
• C15H22N2O · HCl ( milnacipran · hydrochloride)

• 92623-85-3 ( milnacipran )
• 101152-94-7 ( milnacipran · hydrochloride)

N06AX17

White powder ( · milnacipran hydrochloride)

Antidepressant

Serotonin -norepinephrine reuptake inhibitors

• 246.35 g · mol -1 ( milnacipran )
• 282.81 g.mol -1 ( · milnacipran hydrochloride)

179-181 ° C ( · milnacipran hydrochloride)

Water: 19 g · l -1 ( HCl)

Risk

237 mg · kg -1 ( LD50, rat, oral)

Template: Infobox chemical / molecular formula search available

Milnacipran is a drug which has been approved in the EU as an antidepressant in psychiatric therapy and is used in the U.S. for the treatment of fibromyalgia.

Pharmacology

Milnacipran inhibits the central nervous system resume (English: reuptake ) of serotonin and noradrenaline from the synaptic cleft into the presynaptic vesicles. The substance is assigned pharmacologically the serotonin -norepinephrine reuptake inhibitors ( SNRIs). This group also includes venlafaxine and duloxetine. While milnacipran serotonin and norepinephrine reuptake approximately equally blocked, duloxetine has a 10 -fold greater selectivity for serotonin, venlafaxine a 30- fold greater selectivity for serotonin. The substance has no affinity to postsynaptic receptors.

Contraindications ( contraindications)

Milnacipran may not be used in the following cases:

• Use of non- selective MAO inhibitors and selective MAO -A inhibitors: risk of serotonin syndrome
• Selective MAO -B inhibitors, digitalis, 5 -HT1D agonists (eg, sumatriptan ), parenteral epinephrine and norepinephrine and clonidine and related substances: danger of hypertonic crises
• In Benign Prostatic Hyperplasia and other urogenital disorders
• During the lactation period.

The general SSRI and SNRI for judgment given warning of the European Medicines Agency regarding the treatment of children and adolescents is observed.

Interaction with other medicinal

Milnacipran is not metabolised by the cytochrome P450 liver and has none of the CYP systems clinically significant interactions. The plasma levels simultaneously taken medicines are not changed by milnacipran. Interactions with alcohol are not known.

Pharmacokinetics

Milnacipran is well absorbed after oral administration. The bioavailability is approximately 85%, and is not affected by food intake. The peak plasma concentration is achieved by the oral route after about two hours and is approximately 120 ng / ml after a single dose of 50 mg. Concentrations increase in proportion to dose up to 200 mg per administration. Plasma protein binding is low (13% ) and is not saturable. The volume of distribution of milnacipran is approximately 5 l / kg with a total clearance of approximately 40 l / h Renal and non- renal clearance are equivalent. The metabolism of milnacipran is essentially limited to a glucuronic acid conjugation. Very low concentrations of active metabolites without clinical relevance were detected. The plasma half -life is about 8 hours. Excretion is primarily via the kidney (90 % of the administered dose) with a tubular secretion of the unchanged product. After repeated doses Milnacipran is completely excreted two to three days after completion of treatment. Liver failure caused no significant change in the pharmacokinetic properties of the active ingredient. Milnacipran is used for patients with renal insufficiency with caution - the dosage must be reduced if necessary by a prolonged elimination half-life.

Evaluation of antidepressant action

2008 was found in a meta-analysis that in the efficacy and tolerability of milnacipran to other antidepressants, no difference is detectable, and it was found that fewer patients who discontinued treatment due to adverse events. A Cochrane review in 2009 concluded that information on clinically important outcomes such as cost-effectiveness and ability to return to work are missing.

Establishment in the pharmaceutical market

In Austria, the approval was granted as an antidepressant in 1998. In Germany and Switzerland, the manufacturer Pierre Fabre Medicament has not requested. As the antidepressant drug is approved in over 40 countries, including France, Russia, Japan, Finland.

For the indication fibromyalgia syndrome ( FMS), the drug is approved in the U.S. since 2009, however, the approval was denied due to insignificant effects and lack of long-term data in a European population of this in Europe.

Stereoisomerism

2 - ( aminomethyl) -N, N -diethyl -1-phenyl cyclopropancarbamid comprises two stereocenters. Thus, there are the following four forms:

• (1R, 2S)- isomer
• (1S, 2R)- isomer
• (1R, 2R )-isomer
• (1S, 2S )-isomer

Milnacipran drug is a racemate (1:1 mixture) of the ( 1R, 2S )-isomer and the (1S, 2R )-isomer. (1R, 2R)- isomer and the (1S, 2S ) isomer have no practical significance.

Trade names

Ixel (A), Salvella (USA), Toledomin (Japan), JONCIA (Australia), Tivanyl (Mexico), Dalcipran (Chile)